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. 2015 Sep 15;16(1):105.
doi: 10.1186/s12931-015-0264-9.

Uridine Supplementation Exerts Anti-Inflammatory and Anti-Fibrotic Effects in an Animal Model of Pulmonary Fibrosis

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Free PMC article

Uridine Supplementation Exerts Anti-Inflammatory and Anti-Fibrotic Effects in an Animal Model of Pulmonary Fibrosis

Sanja Cicko et al. Respir Res. .
Free PMC article

Abstract

Rationale: Pulmonary fibrosis is a progressive disease with only few treatment options available at the moment. Recently, the nucleoside uridine has been shown to exert anti-inflammatory effects in different animal models, e.g. in acute lung injury or bronchial asthma.

Method: Therefore, we investigated the influence of uridine supplementation on inflammation and fibrosis in the classical bleomycin model. Male C57BL/6 mice received an intratracheal injection of bleomycin on day 0 and were treated intraperitoneally with uridine or vehicle. The degree of inflammation and fibrosis was assessed at different time points.

Results: Uridine administration resulted in attenuated inflammation, as demonstrated by reduced leukocytes and pro-inflammatory cytokines in the broncho-alveolar lavage (BAL) fluid. Furthermore, collagen deposition in the lung interstitium was also reduced by uridine supplementation. Similar results were obtained in a model in which animals received repeated intraperitoneal bleomycin injections. In addition uridine inhibited collagen and TGF-ß synthesis by primary lung fibroblasts, the release of pro-inflammatory cytokines by human lung epithelial cells, as well as the production of reactive oxygen species by human neutrophils.

Conclusion: In summary, we were able to show that uridine has potent anti-inflammatory and anti-fibrotic properties. As uridine supplementation has been shown to be well tolerated and safe in humans, this might be a new therapeutic approach for the treatment of fibrotic lung diseases.

Figures

Fig. 1
Fig. 1
Uridine supplementation decreases inflammation in the early phase after intratracheal bleomycin administration. Animals were treated with i. t. bleomycin on day 0. Uridine or vehicle was administered after 6 h, at day 5 and at day 10. Animals were assessed for inflammation and fibrosis at day 7 and day 14. a BALF differential cell counts. b BALF cytokine levels. c HE stainings of lung sections. d BALF collagen content. e Collagen content on histological lung slides. Data are means ± SEM, n = 4–6 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0,0001. The experiment was repeated twice with similar results
Fig. 2
Fig. 2
Uridine supplementation decreases inflammation and fibrosis in the late phase after intratracheal bleomycin administration. Animals were treated with i. t. bleomycin on day 0. Uridine or vehicle was administered three times a week starting from day 14. Animals were assessed for inflammation and fibrosis at day 30. a BALF differential cell counts. b BALF cytokine levels. c HE stainings of lung sections. d BALF collagen content. e Collagen content on histological lung slides. Data are means ± SEM, n = 4–6 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p <  0,0001. The experiment was repeated twice with similar results
Fig. 3
Fig. 3
Uridine supplementation inhibits inflammation and fibrosis following chronic bleomycin administration. Animals were treated with i. p. bleomycin twice a week over a time period of 4 weeks. Starting from day 14 on animals received either uridine or vehicle for 3 times a week. Animals were assessed for inflammation and fibrosis at day 30. a BALF differential cell counts. b BALF cytokine levels. c HE stainings of lung sections. d BALF collagen content. e Collagen content on histological lung slides. Data are means ± SEM, n = 4–9 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0,0001. The experiment was repeated once with similar results
Fig. 4
Fig. 4
Uridine inhibits the release of pro-inflammatory mediators by human lung epithelial cells. A549 cells were stimulated with bleomycin (1 μg/ml) ± uridine. After an incubation period of 24 h levels of IL-6 and IL-8 in cell culture supernatants were determined by ELISA. Data are means ± SEM, n = 3. *p < 0.05; **p < 0.01
Fig. 5
Fig. 5
Uridine inhibits collagen and TGF-β production by primary lung fibroblasts. Fibroblasts were stimulated as indicated for 8 h, total RNA was isolated. The mRNA specific for collagen and TGF-β was quantified as described. Data are means ± SEM, n = 3. *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 6
Fig. 6
Uridine inhibits production of reactive oxygen species by human neutrophils. Neutrophils were stimulated as indicated and lucigenin-dependent chemiluminescence was measured. a Time courses upon stimulation with vehicle, bleomycin, and bleomycin + uridine. One representative out of 8 experiments is shown. b Maximal chemoluminescence after stimulation with vehicle, bleomycin, and bleomycin + uridine. Data are means ± SEM, n = 7. *p < 0.05; **p < 0.01; ***p < 0.001; ****p< 0,0001

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References

    1. King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378:1949–61. doi: 10.1016/S0140-6736(11)60052-4. - DOI - PubMed
    1. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2014;9:157–79. doi: 10.1146/annurev-pathol-012513-104706. - DOI - PMC - PubMed
    1. Wuyts WA, Agostini C, Antoniou K, Bouros D, Chambers R, Cottin V, et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2012;41(5):1207–1218. - PubMed
    1. Blackburn MR, Lee CG, Young HWJ, Zhu Z, Chunn JL, Kang MJ, et al. Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13 – adenosine amplification pathway. J Clin Invest. 2003;112:332–44. doi: 10.1172/JCI200316815. - DOI - PMC - PubMed
    1. Da Rocha Lapa F, de Oliveira APL, Accetturi BG, de Oliveira Martins I, Domingos HV, de Almeida Cabrini D, et al. Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A(2A) and A (3) receptors. Purinergic Signal. 2013;9(3):325–36. doi: 10.1007/s11302-013-9351-x. - DOI - PMC - PubMed

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